The current therapy for control of elevated intraocular pressure (IOP) or ocular hypertension which is believed to be a factor in the onset and progress of glaucoma is typically effected with a variety of topically applied agents which fall within four categories: .beta.-blockers, sympathomimetic agents, parasympathomimetic agents and cholinesterase inhibitors. The adjuvant oral administration of a carbonic anhydrase inhibitor (CAI) is practiced when the above-described topical agent's side effect limits its use and/or it fails to achieve adequate IOP control. The orally active CAI's can exhibit serious side-effects such as anorexia, gastrointestinal upset and parasthesias. Therefore, an intense and ongoing search has been mounted for a topically active CAI that would not exhibit such side effects due to the route of administration and inherent target organ specificity. This search has resulted in the discovery of a class of compounds by Baldwin et al (U.S. Pat. No. 4,797,413; incorporated herein by reference) of general formula: ##STR1## wherein R and R.sup.1 are lower alkyl, especially dorzolamide, wherein R is ethyl and R.sup.1 is methyl. Additionally, radioisotopically labeled dorzolamide type compounds at the 6-methyl position (6-[.sup.14 CH.sub.3 ]-analogs) are disclosed in Dean D.C., et al., Synthesis and Application of Isotopially Labelled Compounds (1991 ). The compounds are effective for the treatment of elevated intraocular pressure.
The process for making the 6-[.sup.14 CH.sub.3 ]-dorzolamide type compounds teaches an eight step sequence wherein a specific activity of 26.3 mCi/mmol is obtained from a homochiral cyclic sulfone intermediate. As shown in Scheme 1, diastereoselective methylation with [.sup.14 C]methyl iodide of an enantiomerically enriched (4R), t-butyldimethylsilyl protected alcohol (1) produced a 15:1 mixture of the 4R,6S::4R,6R diastereomers e2 and 3) in near quantitative yield. While this asymmectric alkylation provides an entry to the desired radiotracer, the inherent low specific activity of .sup.14 C-labeled radiotracers (only ca. 60 mCi/mmol for one .sup.14 C atom per label compound molecule) is inadequate for some biological reactions and biochemical studies.
The instant process results in the sysnthesis of a 6-[C.sup.3 H.sub.3 ]-dorzolamide with a specific activity 2000 fold higher than the [.sup.14 C]dorzolamide. Additionally, in the .sup.14 C-sequence the functional group elaborations after the methylation are lengthy and involve procedures which are not easily amenable to use in a sub-milligram scale radiolabeling with other radiotracers such as tritium. Moreover, the instant process (see Scheme 2 below) is unlike the radiosynthesis of the [.sup.14 C]dorzolamide (Scheme 1), in which the creation of both chiral centers and sophisticated separations of the resulting four isomers were involved. The instant synthesis of 6-[C.sup.3 H.sub.3 ]-dorzolamide starts with an optically enriched 4S-ethylamino precursor (6 of Scheme 2). This allows the methylated, diastereomeric products to be easily purified with conventional high performance liquid chromatography (HPLC) to afford the instant 6-[C.sup.3 H.sub.3 ]-dorzolamide (10) in high optical purity as well as its 4S, 6R isomer. ##STR2##
Other processes known in the art are disclosed in U.S. Pat. Nos. 4,968,815; 4,968,814; 5,157,129 and co-pending U.S. application No. 08/035,523. However, these processes involve procedures that are not easily amenable for the preparation of 6-[C.sup.3 H.sub.3 ]-dorzolamide, especially at the no-carder-added scale. Compared with all the above-mentioned processes, the present invention offers a shorter and more advantageous approach to prepare high specific activity 6-[C.sup.3 H.sub.3 ]-dorzolamide and is more practical at the no-carder-added scale. It also offers an altemative approach for the preparation of carbonic anhydrase inhibitors described in U.S. Pat. No. 4,797,413 and the corresponding 6R-isomers.